Chronic p53-independent p21 expression causes genomic instability by deregulating replication licensing

• Published in: Nature cell biology Vol. 18; no. 7; pp. 777 - 789
• Main Authors: Galanos, Panagiotis, Vougas, Konstantinos, Walter, David, Polyzos, Alexander, Maya-Mendoza, Apolinar, Haagensen, Emma J., Kokkalis, Antonis, Roumelioti, Fani-Marlen, Gagos, Sarantis, Tzetis, Maria, Canovas, Begoña, Igea, Ana, Ahuja, Akshay K., Zellweger, Ralph, Havaki, Sofia, Kanavakis, Emanuel, Kletsas, Dimitris, Roninson, Igor B., Garbis, Spiros D., Lopes, Massimo, Nebreda, Angel, Thanos, Dimitris, Blow, J. Julian, Townsend, Paul, Sørensen, Claus Storgaard, Bartek, Jiri, Gorgoulis, Vassilis G.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.07.2016; Nature Publishing Group
• Subjects: 13/109; 13/31; 13/89; 14/28; 49/15; 49/31; 49/39; 49/47; 49/88; 49/91; 631/1647/2017; 631/337/1427; 631/337/151/2356; 631/337/474; 631/67; Analysis; Cancer; Cancer Research; Cancer therapies; Cell Biology; Cells, Cultured; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Cyclin-dependent kinases; Cyclins - genetics; Cyclins - metabolism; Deregulation; Developmental Biology; DNA replication; DNA Replication - genetics; Genetic aspects; Genomic Instability - genetics; Genomics; Humans; Kinases; Licenses; Licensing; Life Sciences; Medical research; Medicin och hälsovetenskap; Medicine; Neoplasms - genetics; Physiological aspects; Senescence; Stem Cells; Tumor proteins; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumors; Ubiquitin; Greece; Denmark; United Kingdom > UK; United States > US; South Carolina; Spain
• ISSN: 1465-7392; 1476-4679; 1476-4679
• DOI: 10.1038/ncb3378

The cyclin-dependent kinase inhibitor p21 WAF1/CIP1 (p21) is a cell-cycle checkpoint effector and inducer of senescence, regulated by p53. Yet, evidence suggests that p21 could also be oncogenic, through a mechanism that has so far remained obscure. We report that a subset of atypical cancerous cells strongly expressing p21 showed proliferation features. This occurred predominantly in p53-mutant human cancers, suggesting p53-independent upregulation of p21 selectively in more aggressive tumour cells. Multifaceted phenotypic and genomic analyses of p21-inducible, p53-null, cancerous and near-normal cellular models showed that after an initial senescence-like phase, a subpopulation of p21-expressing proliferating cells emerged, featuring increased genomic instability, aggressiveness and chemoresistance. Mechanistically, sustained p21 accumulation inhibited mainly the CRL4–CDT2 ubiquitin ligase, leading to deregulated origin licensing and replication stress. Collectively, our data reveal the tumour-promoting ability of p21 through deregulation of DNA replication licensing machinery—an unorthodox role to be considered in cancer treatment, since p21 responds to various stimuli including some chemotherapy drugs. Galanos and colleagues observe p21 accumulation in proliferating cancer cells, and show that in cultured p53-null cells, p21 can cause genomic instability by perturbing replication licensing through inhibition of the CRL4-CDT ubiquitin ligase.